Bowel cleansing composition

ABSTRACT

A bowel cleansing composition includes as a first cleansing ingredient, a specific sugar alcohol such as xylitol, sorbitol, etc., as a second cleansing ingredient glycerol, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol, as a second cleansing ingredient ascorbic acid or a mixture of ascorbic acid and a salt of ascorbic acid, as a third cleansing ingredient picosulfate, and an aqueous solvent, wherein the concentration of the first cleansing ingredient is 10 g/L to 500 g/L based on the total composition, the concentration of the second cleansing ingredient is 15 g/L to 500 g/L based on the total composition, the concentration of the third cleansing ingredient is 1 mg/L to 100 mg/L based on the total composition, and the volume of the aqueous solvent is 0.1 L to 1.0 L.

FIELD OF THE INVENTION

The present invention relates to a bowel cleansing composition. Morespecifically, the present invention relates to a novel bowel cleansingcomposition comprising high concentrations of a specific sugar alcoholand ascorbic acid in addition to picosulfate that is a laxative agent soas to improve the ease of administration by reducing the total dosageand yet improve bowel cleansing efficacy while ensuring safety.

BACKGROUND OF THE INVENTION

According to the reports from the World Cancer Research FundInternational, colon cancer is the third most common cancer worldwidewith incidences of colon cancer during the year 2012 estimated to be 1.4million worldwide and expected to be 2.4 million in the year 2035. Forthe diagnosis of colon cancer, colonoscopy is essential. Moreover,colonoscopy is very important because colon cancer can be prevented ifcolon polyps, which are considered to be the precursor of colon cancer,are detected during colonoscopy and removed.

For accurate colonoscopy examination, bowel cleansing prior to theprocedure is essential; since stool may be retained inside the coloneven after fasting for days, it is necessary to cleanse the colonthoroughly by artificial methods prior to the examination. For thispurpose, methods have been developed where cleansing liquids comprisedof laxative agents are ingested to empty the colon. An ideal bowelcleansing agent should have high cleansing power, ease ofadministration, as well as safety.

Firstly, high cleansing power is an essential requirement for anaccurate colonoscopy procedure. If too much residue remains after bowelcleansing, it is difficult to perform an accurate examination, and thepoor visualization increases the risk of complications such asperforation, and sometimes the painful bowel procedure has to berepeated, which might result in the patient's refusal or avoidance ofthe examination. Thus, reliable cleansing efficacy is the most importantrequirement.

Secondly, the ease of administration is determined by the volume of thebowel cleansing agent to be ingested, the taste of the agent, and theoccurrence of discomforts such as nausea, vomiting, and abdominal painfollowing the ingestion of the agent. Even if a bowel cleansing agenthas excellent cleansing power, if its administration is difficult, onecannot successfully complete the intake process in accordance with thedosing regimen, resulting in inadequate bowel cleansing. In addition,the unpleasant experience with bowel cleansing often leads to therefusal of repeat examination, and rumors about the difficulties ofadministration may impede the popularization of colonoscopies harmingpublic health.

Thirdly, as a safety requirement, bowel cleansing should minimizetemporary disorders and should not cause irreversible chronic disorders.

Early regimens involved ingesting a large volume of up to 7-12 L ofsolutions like saline solutions as bowel cleansing agents. However,administration of such cleansing preparations was accompanied by a greatdeal of pain and difficulties.

Later, bowel cleansing preparations using 2 L of 10% mannitol, a sugaralcohol, was introduced and garnered much expectation. However, colonicgas explosions during colonic surgery or therapeutic colonoscopy aftermannitol preparation have been reported and the use of mannitol is nowavoided. Bowel cleansing preparations with sorbitol have also beenconsidered to be inappropriate in most advanced countries including theU.S. and Europe due to similar risks.

In the 1980s, bowel cleansing preparations comprising the ingestion ofpolyethylene glycol (PEG) formulated into a 4 L solution were developed.PEG formulations are still the most commonly used bowel cleansing agentsworldwide.

The most serious problems with PEG preparations were their very largevolume amounting to 4 L and difficulties of ingestion due to theirdisgusting taste. Such difficulty of ingestion gave rise to thewide-spread negative perception of bowel preparation, which has ledpeople to fear or avoid colonoscopies.

Thus, various attempts have been made to reduce the volume of the PEGpreparations to be ingested. For example, the required volume of thediluted PEG solution may be reduced to 3 L by including a stimulantlaxative such as bisacodyl tablets in the regimen such that it isadministered 6-12 hours prior to the ingestion of the PEG solution, orusing a magnesium citrate (Trade name Citromag®) solution incombination, or adding ascorbic acid (Trade name MoviPrep®). In the caseof MoviPrep® type bowel cleansing preparations, ascorbic acid and sodiumascorbate are added to make up for the anticipated reduction incleansing efficacy. However, as the total amount of PEG contained inthese bowel cleansing preparations is 200 g, the PEG content hasdecreased by only 15.3%, compared to the 236 g contained in the COLYTEpowder which is to be administered in a 4 L volume. Thus, despite thedecrease in the total volume of the diluted solution to be ingested,complaints of patient discomfort are more common than in the case of theCOLYTE powder 4 L regimen because PEG is concentrated 1.7-fold.

In addition to such difficulties of ingestion, PEG preparations have notachieved satisfactory bowel cleansing power. Various studies show thatthe percentage of bowel cleansing with a PEG formulation achieving acleansed level adequate for colonoscopy is approximately 70%. Suchinsufficient cleansing by PEG formulations has been demonstrated by anumber of published studies. For instance, a study has reported thatcolonoscopy was hindered by the residual solid stool in the colon in47.1% of patients who had their bowel cleansed with the PEG formulation“Colyte” <“Comparison between Conventional 4 L Polyethylene Glycol andCombination of 2 L Polyethylene Glycol and Sodium Phosphate Solution asa Colonoscopy Preparation”, Seoul National University Bundang Hospital,Department of Internal Medicine, Seoul National University College ofMedicine and Liver Research Institute, Jung Won Lee et al., Korean JGastroenterology, 56, 299-306, 2010>.

In order to resolve such ingestion problems with the PEG preparations,picosulfate preparations comprising magnesium citrate were developed asbowel cleansing preparations. A big advantage with picosulfatepreparations is that they have greatly improved taste and thus, unlikePEG preparations, their consumption causes little discomfort due tounpleasant taste. For that reason, picosulfate preparations are mostcommonly used in Europe, but their relatively poor bowel cleansing poweris the biggest problem with these preparations. The recommended regimenfor Ferring's Prepopik® (sodium picosulfate, magenisum oxide, andanhydrous citric acid) approved by the U.S. FDA indicates the totalvolume of ingestion amounting to 2.22 L, and according to actual use ofthis preparation it has been found to be problematic due to itsrelatively poor cleansing power compared to PEG solutions.

For such reasons, Picolight®, which has the same composition asPrepopik®, is often used in a total volume of 3.5 L in clinicalsettings, which is 1.5-fold higher than its recommended dose.

Moreover, picosulfate-containing bowel cleansing agents do not containelectrolytes and thus they rarely cause hyponatremia or hypopotassemiadue to overdose, but severe side effects such as spasm, etc., have beenreported. Due to the incorporation of magnesium into this preparation,hypermagenesemia may occur, and thus patients with renal disorders arebanned from using the preparation.

Thus, picosulfate-containing bowel cleansing agents developed forsolving the ingestion difficulties with PEG preparations have improvedcompliance but show poor bowel cleansing efficacy. Consequently,patients still have to ingest large amounts ranging from 2.3 L to 3.5 L,and there exist problems of electrolyte abnormalities andhypermagenesemia.

Attempts to overcome the above limitations of known bowel cleansingpreparations have not been successful and, consequently, there is astrong need for the development of a novel bowel cleansing compositionthat has reliable cleansing powder, ease of administration, minimal sideeffects, and is safe.

DISCLOSURE OF THE INVENTION

In order to solve the problems in the prior art described above, thepresent invention has the objective of providing a novel bowel cleansingcomposition that is equipped not only with excellent cleansing efficacyto greatly improve the proportion of adequate bowel preparation that isstill at about 70% at most but also with ease of administration owing tothe improved taste as well as safety for the human body.

The present invention has another objective of providing a novel bowelcleansing composition which allows for economical mass production andcommercialization.

The bowel cleansing composition according to the invention comprises asa first cleansing ingredient at least one sugar alcohol selected fromxylitol, sorbitol, glycerol, erythritol, threitol, arabitol, ribitol,mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt,maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol; as asecond cleansing ingredient ascorbic acid or a mixture of ascorbic acidand a salt of ascorbic acid; as a third cleansing ingredientpicosulfate; and an aqueous solvent, wherein the concentration of thefirst cleansing ingredient is 10 g/L to 500 g/L based on the totalcomposition, the concentration of the second cleansing ingredient is 15g/L to 500 g/L based on the total composition, the concentration of thethird cleansing ingredient is 1 mg/L to 100 mg/L, and the volume of theaqueous solvent is 0.1 L to 1.0 L.

By combining specific concentrations of a sugar alcohol, ascorbic acid,and picosulfate, the bowel cleansing composition according to thepresent invention displays superior cleansing efficacy as well asimproved taste compared to existing bowel cleansing compositions. Thebowel cleansing composition according to the present invention alsogreatly enhances the ease of administration and compliance bysignificantly reducing the volume of ingestion. In addition, the bowelcleansing composition according to the present invention improvespatient discomfort by minimizing discomforts such as nausea, abdominalpain and vomiting during its consumption. By incorporating bicarbonatessuch as sodium bicarbonate, potassium bicarbonate, etc., electrolyteabnormalities such as hyponatremia, hypopotassemia, etc., which occurredwith the existing bowel cleansing agents comprising picosulfate, can beprevented. Since the bowel cleansing composition of the presentinvention does not contain any magnesium, it can be safely used withoutsevere side effects in patients with renal disorders.

In addition, by combining specific concentrations of a sugar alcohol andascorbic acid, the present invention achieves superior cleansingefficacy and antibacterial effect relative to the volume of the consumedfluid, eliminating the risk of production of combustible gases in thecolon after bowel cleansing preparation ensuring safety in the humanbody.

In particular, the most stressful part about the bowel cleansingpreparation procedure from the viewpoint of the patients includes largevolumes of ingestion, unpleasant taste, discomforts such as abdominalpain and vomiting. Picosulfate-containing bowel cleansing agents improvediscomfort after administration but are still inconvenient in that largevolumes amounting to 3.5 L need to be ingested due to their insufficientcleansing efficacy. By incorporating specific amounts of a sugar alcoholand ascorbic acid instead of magnesium citrate which had beenadditionally used in the existing picosulfate preparations, the presentinvention enhances bowel cleansing efficacy, thereby reducing the volumeof ingestion to 2 L or less including water and thus leading to improvedcompliance. As such problems were solved, less patients complained ofpain during administration. The present invention is significant inthat, despite a greatly reduced volume being consumed, bowel cleansingefficacy was more improved and the potential risk of the generation ofintestinal combustible gas can be eliminated as much as possible byusing a specific sugar alcohol in combination with ascorbic acid.

As described above, the bowel cleansing composition of the presentinvention can make the bowel preparation procedure significantly easierand safer, thereby greatly contributing to the popularization ofcolonoscopy and, as a result, maximizing the early detection of coloncancer as well as the prevention of colon cancer by polypectomy. Thebowel cleansing composition of the present invention may also beutilized in treating and alleviating constipation.

The preparation process of the invention allows for economical massproduction and commercialization of the bowel cleansing composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 and FIG. 2 are photographs obtained from the respectivelaboratories which show the results of culturing intestinal bacterialafter treatment with the bowel cleansing compositions according to oneExample and the Comparative Examples.

FIG. 3 shows photographs representing the cleanliness of the colonfollowing the ingestion of the bowel cleansing compositions according toone Example and the Comparative Examples.

FIG. 4A and FIG. 4B show graphs representing the rates of effective andinsufficient bowel cleansing following the consumption of the bowelcleansing compositions according to one Example and the ComparativeExamples.

FIG. 5 is a photograph showing a substantial amount of intracolonicbubbles generated after consumption of a bowel cleansing compositionprepared according to prior art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in detail with reference tothe drawings.

The bowel cleansing composition according to the present inventioncomprises as a first cleansing ingredient at least one sugar alcoholselected from xylitol, sorbitol, glycerol, erythritol, threitol,arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol,volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol,and polyglycitol; as a second cleansing ingredient, ascorbic acid or amixture of ascorbic acid and a salt of ascorbic acid; as a thirdcleansing ingredient picosulfate; and an aqueous solvent, wherein theconcentration of the first cleansing ingredient is 10 g/L to 500 g/Lbased on the total composition, the concentration of the secondcleansing ingredient is 15 g/L to 500 g/L based on the totalcomposition; the concentration of the third cleansing ingredient is 1mg/L to 100 mg/L, and the volume of said aqueous solvent is 0.1 L to 1.0L.

Sugar alcohols used in the present invention as the first cleansingingredient are a cleansing ingredient that works as a laxative when usedat a high concentration. The sugar alcohol used as the first cleansingingredient for the present invention is one or more selected fromxylitol, sorbitol, glycerol, erythritol, threitol, arabitol, ribitol,mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt,maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. Inone aspect of the present invention, sugar alcohol used as the firstcleansing ingredient may include xylitol or sorbitol or a mixture ofxylitol and sorbitol.

With respect to the safety of sugar alcohols, along with mannitol,sorbitol has been deemed as a substance that should not be used forbowel preparation after an incidence of colonic gas explosion during acolopolypectomy procedure following bowel preparation using sorbitol wasreported.

However, a review article by Ladas et al. shows that such incidence ofexplosion is not limited to mannitol or sorbitol, but occurs also afterbowel preparation with a PEG formulation or a phosphate formulation.According to Ladas et al., a total of 20 gas explosions associated withbowel preparations were reported between 1952 and 2006, including fourexplosions during colopolypectomy of which two involved bowelpreparation with PEG formulations, one with a phosphate formulation andanother with mannitol  “Colonic gas explosion during therapeuticcolonoscopy with electrocautery”, Ladas S D, Karamanolis G, Ben-SoussanE., World J Gastroenterol, 13, 5295-8, 2007>.

Colonic gas explosions during surgery or therapeutic endoscopy afterbowel preparation are believed to be caused by the combustible gaseshydrogen and methane produced by the fermentation of sugar alcohols suchas mannitol and sorbitol by intestinal bacteria. The explosive rangesfor methane and hydrogen are 5-15 vol % and 4-75 vol %, respectively.

However, it has been demonstrated that hydrogen and methane gases aremore likely to be produced when there are residues in the colon due toinadequate cleansing. It has been known that colonic gas explosionsoccurred not only with mannitol or sorbitol, but also after bowelpreparation with formulations of PEG, which is another sugar alcohol, orphosphate, which is not a sugar alcohol. These facts indicate that thecause of colonic gas explosion cannot be limited to the use ofparticular colon cleansing preparations. Rather, the quality of coloncleansing has a significant effect in this regard. This is because wheninadequate bowel cleansing leaves a lot of intestinal bacteria behind,substances such as sugar alcohols in the residual stool and the bowelcleansing solution are excessively degraded, producing hydrogen andmethane in explosive concentrations.

Indeed, Nunes et al. reported that the cleansing efficacy of mannitol isinferior to PEG formulations, with the rate of adequate bowel cleansingbeing only 75% for mannitol as compared with 90% for PEG formulationswhen evaluated according to a scale proposed by the authors<“Comparative evaluation of bowel preparation for colonoscopy usingmannitol and polyethylene glycol—a prospective study”, Nunes B L, Belo SG, Pessoa M H, Lins Neto M A., Rev Bras Coloproctol, 28, 294-8, 2008>.

Given these observations, previously reported gas explosions after bowelpreparation with mannitol or sorbitol are believed to have been affectedby inadequate bowel cleansing.

However, by using a sugar alcohol as a first cleansing ingredient incombination with a second cleansing ingredient such as ascorbic acid,etc., and picosulfate as a third cleansing ingredient in specificconcentrations, the present invention achieves superior cleansingefficacy and antibacterial effect relative to the volume of consumedfluid, eliminating the risk of explosion arising from inadequate bowelpreparation ensuring safety.

The concentration of the first cleansing ingredient used in the presentinvention ranges from 10 g/L to 500 g/L, 20 g/L to 200 g/L, or 50 g/L to150 g/L based on the total preparation, without limitation. If theconcentration of the first cleansing ingredient is higher than the aboverange, production of the combustible gases hydrogen and methane mayincrease. If the concentration of the first cleansing ingredient islower than the above range, it may lead to incomplete bowel cleansing.

Ascorbic acid, which is used as the second cleansing ingredient in thepresent invention, is a water-soluble vitamin known as vitamin C, anessential vitamin playing various roles in maintaining health. With anincreasing interest in ascorbic acid, a variety of specialty beveragescontaining ascorbic acid are being marketed. These specialty beveragesare manufactured to contain ascorbic acid at concentrations up to 10mg/mL (i.e., 10 g/L).

In the present invention, however, ascorbic acid is the main cleansingingredient which is used in a high concentration to work as a laxativeand its antibacterial activity inhibits intestinal bacteria such thatthe production of colonic gases is minimized. For this purpose, thesecond cleansing ingredient is incorporated at a high concentration of15 g/L to 500 g/L, 20 g/L to 300 g/L, or 30 g/L to 200 g/L based on thetotal composition. If the concentration of the second cleansingingredient is higher than the above range, the excessively high acidityof the preparation may lead to excessive sour taste, making it difficultto consume the preparation, and may severely stimulate the stomach tocause nausea, retching, vomiting, and heartburn during the consumptionof the preparation. On the other hand, if the concentration of thesecond cleansing ingredient is lower than the above range, the reducedantibacterial effect may lead to the excessive production of combustiblegases in the colon.

A salt of ascorbic acid used as the second cleansing ingredient in thepresent invention refers to an alkaline metal or alkaline earth metalsalt of ascorbic acid. Examples of the alkaline metal include, but arenot limited to, sodium or potassium, and examples of the alkaline earthmetal include, but are not limited to, calcium. The salt of ascorbicacid used in the present invention may be sodium ascorbate or calciumascorbate.

A salt of ascorbic acid reduces the acidity of a solution compared toascorbic acid alone, enhancing the bowel cleansing efficacy byinhibiting the absorption of ascorbic acid which is known to increasewith acidity.

When the second cleansing ingredient is a mixture of ascorbic acid and asalt of ascorbic acid, the mass ratio of ascorbic acid to the salt ofascorbic acid may range from 99:1 to 60:40. If the mass ratio ofascorbic acid to the salt of ascorbic acid is outside the above range,excessive amounts of sodium, calcium, potassium or magnesium may beabsorbed to the body, causing electrolyte abnormalities or resulting inhypercalcemia or hypermagnesemia.

Picosulfate used as the third cleansing ingredient in the presentinvention is used as a stimulant laxative. Picosulfate is usuallyadministered once or twice daily at a dose of 7.5 mg at one time. Theconcentration of picosulfate used as the third cleansing ingredient inthe present invention may be 1 mg/L to 100 mg/L, 10 mg/L to 80 mg/L, or15 mg/L to 70 mg/L, based on the total composition.

The bowel cleansing composition of the present invention mayadditionally comprise an anti-foaming agent in order to remove colonicgases or bubbles frequently seen after bowel preparation. In one aspectof the present invention, examples of suitable anti-foaming agentincludes, without limitation, simethicone.

In general, if a substantial amount of bubbles appear during screeningcolonoscopy, a diluted simethicone solution is prepared and injectedinto the colon through a small channel in the scope. Another approachinvolves separate administration of a separately provided simethiconepreparation at the last stage of bowel preparation. However, whendiluted simethicone is injected through a channel in the scope duringthe procedure, the area that can be covered by a single application ofdiluted simethicone is very limited. Thus, if the bubbles are formedacross a large area, inconvenience arises as the application of dilutedsolution may need to be repeated as many as ten times or more. Even whenthe simethicone preparation is separately administered at the last stageof bowel preparation, the volume of the preparation is typically assmall as 10 ml, which may be insufficient to prevent the formation ofbubbles throughout the colon.

To address this problem, the present invention incorporates a dilutedanti-foaming agent such as simethicone into the bowel cleansingcomposition so that foaming is very effectively inhibited across theregions of colon reached by the bowel cleansing liquid even with a smallvolume of the anti-foaming agent.

The concentration of the anti-foaming agent used in the presentinvention may be 100 mg/L to 2 g/L, 150 mg/L to 1.5 g/L, or 200 mg/L to1 g/L based on the total preparation in the case of simethicone, but isnot limited to the above ranges in the case of anti-foaming agents otherthan simethicone. If the concentration of the anti-foaming agent exceedsthe upper limit of the above range, it may cause adverse effects such asabdominal pain, rash, swelling of the face or tongue, breathingdifficulties, etc.

Aqueous solvents that can be used in the present invention includewater, carbonated water, alkaline ionized water, and beverages, forexample. There is no particular limitation on the kind of beverage aslong as the effect of the present invention can be achieved. Examples ofbeverages include coffee, various juices, cola, clear sodas, and gin andtonic. In one aspect of the present invention, carbonated water oralkaline ionized water can be used as the aqueous solvent. Workingindependently as a laxative, carbonated water is known to be effectivein improving constipation in elderly people suffering from chronicconstipation. Alkaline ionized water may increase the cleansing efficacyby partially neutralizing the acidity of the bowel cleansing compositionof the present invention, leading to reduced absorption of ascorbicacid.

The volume of the aqueous solvent can be, without limitation, 0.1 L to1.0 L, 0.1 L to 0.9 L, 0.2 L to 0.8 L, or 0.3 L to 0.7 L. If the volumeof the solvent is less than 0.1 L, ingredients may not be completelydissolved in the solvent. If the volume of the solvent is greater than1.0 L, the large volume may lead to reduced compliance.

The bowel cleansing composition of the present invention mayadditionally comprise ingredients for improving compliance andalleviating upper gastrointestinal symptoms such as nausea, retching andvomiting that are frequently observed during bowel preparation.

Because the bowel cleansing composition of the present inventioncontaining a large amount of ascorbic acid and citric acid is high inacidity and may be difficult to consume due to excessive sour taste, itmay comprise a bicarbonate salt such as sodium bicarbonate and potassiumbicarbonate to neutralize the acidity.

Sodium bicarbonate can be used at a concentration ranging from 0.1 g/Lto 10 g/L based on the total preparation. If used beyond the aboverange, it may lead to reduced compliance due to excessive saltiness andcause hypernatremia. Potassium bicarbonate can be used at aconcentration ranging from 0.1 g/L to 20 g/L based on the totalpreparation. If used beyond the above range, it can cause hyperkalemiadue to the intake of potassium exceeding its daily recommended dose.Hyperkalemia poses the risk of heart disorders, for example.

The bowel cleansing composition of the present invention may furthercomprise an extract, powder or concentrate of ginger, peppermint,chamomile or the like in the form of aqueous solution for the purpose ofenhancing the compliance by alleviating symptoms such as nausea,vomiting and abdominal pain. These ingredients work as gastrointestinalsoother and can be incorporated at a concentration of 5 g/L to 50 g/Lbased on the total bowel cleansing composition. If used excessivelybeyond the above range, such gastrointestinal soothers may reduce thecleansing efficacy by inhibiting bowel movement.

The bowel cleansing composition of the present invention may furthercomprise known cleansing ingredients or adjuncts for augmenting thecleansing effect. Examples of additional cleansing ingredients andadjuncts include citric acid, magnesium component such as magnesiumoxide, docusate sodium, senna extract (e.g., sennoside), aloe extract(e.g., aloin), garlic extract (e.g., alliin and allicin) etc. andpectin, zinc component such as zinc oxide, caffeine, etc.

Citric acid is a natural substance present in citrus fruits in highconcentrations. It makes sour taste and is used as a preservative in avariety of beverages and food. Citric acid is classified as a very safesubstance, and the FDA and the FAO/WHO have recognized that theingestion of excessive amounts of citric acid causes little harm. In thebowel cleansing composition of the present invention, citric acid can beincorporated as an additional cleansing ingredient working as alaxative. In this case, the concentration of citric acid may be 1 g/L to15 g/L based on the total preparation. If its concentration exceeds theabove range, patient compliance may be reduced due to heartburn andstrong sour taste.

Magnesium is also a substance than can function as a laxative. However,it should be used with caution in people with renal disorders becauseadministering an excess amount greater than 3 g at one time may causeadverse effects from hypermagnesemia.

Pectin and zinc can enhance the laxative effect of ascorbic acid byinhibiting its gastrointestinal absorption. Pectin can be used at aconcentration of 0.1 g/L to 2 g/L based on the total preparation, andmay not be dissolved if used at a concentration greater than the aboverange. Zinc oxide can be used at a concentration of 10 mg/L to 400 mg/Lbased on the total preparation, and its excessive intake beyond theabove range may cause vomiting, retching, etc.

Caffeine may be used to fight the sluggishness that may be felt duringbowel preparation and enhance the cleansing efficacy. Up to 30 mg ofcaffeine can be used based on the total preparation. Excessive intake ofcaffeine beyond the above range can cause tachycardia, anxiety, sleepdisturbance, etc.

Substances that may be used as adjunctive laxatives also includedocusate sodium (10 mg/L to 400 mg/L. Excessive intake can causevomiting, abdominal pain, etc.), senna extract (sennoside, 10 mg/L to 50mg/L, Excessive intake can cause vomiting, abdominal pain, etc.), aloeextract (aloin, 10 mg/L to 50 mg/L. Prolonged excessive intake can causereduced bowel function), garlic extracts (alliin and allicin, 10 mg/L to5 g/L, Excessive intake can cause severe abdominal pain and vomiting),and the like.

The bowel cleansing composition of the present invention may includesweeteners to improve taste. Examples of suitable sweeteners include,without limitation, sucralose, maltodextrin, glucose, sucrose, dextrose,saccharin, aspartame, and stevia. Such sweeteners can be used in a rangefrom 0.01 mg/L to 10 g/L based on the total bowel cleansing composition.Using an excessive amount beyond the above range may cause discomfortssuch as nausea and retching.

The bowel cleansing composition of the present invention mayadditionally include suitable amounts of edible fruit flavorings toenhance compliance. Such fruit flavorings may be strawberry flavor,orange flavor, apple flavor, grape flavor, lemon flavor, banana flavor,cherry flavor, etc.

The bowel cleansing composition of the present invention mayadditionally comprise a suitable amount of antioxidant to prevent theoxidation of ascorbic acid. Such antioxidant includes, withoutlimitation, ferulic acid, amino acids such as glycine and histidine,hyaluronic acid, and tocopherol.

In addition, the bowel cleansing composition of the present inventionmay additionally comprise a chelating agent to chelate the trace amountsof iron and copper ions potentially contained in the aqueous solvent.Examples of such chelating agents include, without limitation, theVersene CA chelating agent (The Dow Chemical Company).

The bowel cleansing composition according to the present invention canbe a one-part product or a two-part product.

In one aspect of the present invention, the bowel cleansing compositioncan be packaged as a one-part product in which the entire ingredientsincluding a first cleansing ingredient, a second cleansing ingredient,and a third cleansing ingredient, and, as necessary, an anti-foamingagent, a gastrointestinal soother, and other additives are packaged in acontainer together with an aqueous solvent.

In another aspect of the present invention, the bowel cleansingcomposition can be packaged as a two-part product. For example, thefirst cleansing ingredient, the second cleansing ingredient, and thethird cleansing ingredient may be packaged together while the aqueoussolvent is separately packaged; the second cleansing ingredient and theaqueous solvent are packaged together while the first cleansingingredient and the third cleansing ingredient are separately packaged;the first and third cleansing ingredients and the aqueous solvent arepackaged together while the second cleansing ingredient is separatelypackaged; the first and third cleansing ingredients and part of theaqueous solvent are packaged together while the second cleansingingredient and part of the aqueous solvent are packaged together; or thefirst, second, and third cleansing ingredients and part of the aqueoussolvent may be packaged together while the remaining part of the aqueoussolvent is separately packaged, but not limited thereto. In addition,anti-foaming agent, gastrointestinal soother, and other additives can beincorporated into the two-part product, as necessary, in variouscombinations.

A method of formulating the bowel cleansing composition as a two-partproduct that is packaged in the form of highly concentrated solution anda vehicle and using the product is now explained. For example, theentire ingredients including the first cleansing ingredient, secondcleansing ingredient and third cleansing ingredient, and, if necessary,the anti-foaming agent, gastrointestinal soother, and other additivesare dissolved in a minimal amount of an aqueous solvent to give a highlyconcentrated solution, and users may dilute the solution in a beverage(making up the remaining volume as an aqueous solvent) they have chosenas vehicle. In such a case, the volume of the aqueous solvent forforming the highly concentrated solution may be 0.05 L to 0.2 L, and theamount of the beverage of the user's choice, i.e., vehicle may be theremaining volume for an aqueous solvent. If necessary, each solidingredient of the composition is separately packaged as well as theaqueous solvent, and users can mix the entire ingredients at the time ofingestion. Various other forms of packaging can also be used and theform of the two-part product is not limited by the packaging methodsdescribed above.

In manufacturing the bowel cleansing composition according to thepresent invention, the entire ingredients including the first cleansingingredient, the second cleansing ingredient, and the third cleansingingredient, and as necessary, the anti-foaming agent, gastrointestinalsoother, and other additives can be mixed with the aqueous solvent atthe same time, or each ingredient can be separately prepared and thenmixed stepwise.

For example, a process for preparing the bowel cleansing compositionaccording to the present invention may comprise the steps of forming afirst mixture comprising a sugar alcohol as a first cleansingingredient; forming a second mixture comprising ascorbic acid orascorbic acid and a salt of ascorbic acid as a second cleansingingredient; forming a third mixture comprising picosulfate as a thirdcleansing ingredient; as necessary, forming a fourth mixture comprisingan anti-foaming agent; as necessary, forming a fifth mixture comprisinga gastrointestinal soother; and mixing the first mixture to fifthmixture with an aqueous solvent to form a bowel cleansing composition.

In another aspect of the present invention, a process for preparing thebowel cleansing composition of the present invention may additionallyinclude the steps of mixing in advance the first mixture to fifthmixture in any combinations prior to mixing the first, second, and thirdmixtures, and as necessary the fourth and fifth mixtures, with anaqueous solvent.

In a further aspect of the present invention, a process for preparingthe bowel cleansing composition of the present invention may involve,for example, preparing in advance a highly concentrated solutioncomprising the first, second, and third mixture, and as necessary, thefourth and fifth mixtures, and part of the aqueous solvent, and thenadjusting the solution to the above-described specific concentrationsand quantities by diluting with various beverages at the time ofingestion. In this case, the type of beverage that users can choose as avehicle is not particularly limited as long as it is an aqueous solvent,including water, carbonated water, alkaline ionized water and abeverage, etc., and the beverage may be the same as or different fromthe aqueous solvent in the highly concentrated solution. There is noparticular limitation on the kind of beverage as long as the effect ofthe present invention can be achieved. Examples of beverages includedrip coffee, various juices, cola, clear sodas, and gin and tonic.

In the process for preparing the bowel cleansing composition of thepresent invention, the method of mixing for the individual ingredients,particle shape and size of solids, pH, preparation temperature,agitation conditions, containers, packaging material, vacuum packagingor gas-substituted packaging, and other packaging specifics may beadjusted as necessary depending on the form, type, shipping and storagemethod of the bowel cleansing composition to be prepared.

A dosing regimen for the bowel cleansing composition of the presentinvention may involve, without limitation, consuming 50-100 cc of thecomposition every 5-10 minutes for a total of 5-10 doses, starting at3-5 hours before the scheduled colonoscopy depending on the bowelsensitivity of the subject. While not intended to be limiting, the bowelcleansing composition of the present invention may be ingested over atime period of, for example, 1 hour to 1.5 hour and a suitable amount ofbottled water or the like may be additionally taken in case of thirst.

By comprising specific concentrations of a sugar alcohol, ascorbic acid,and picosulfate, the bowel cleansing composition of the presentinvention displays enhanced bowel cleansing efficacy despite a greatlyreduced volume of ingestion. The bowel cleansing composition of thepresent invention also achieves convenience of administration byrequiring a very small volume of ingestion. In addition, the bowelcleansing composition of the present invention causes no or minimaldiscomfort such as nausea, retching, and bloating as it does not containunpalatable ingredients, and is safe as it inhibits the production ofcombustible gases in the colon.

The preparation process of the present invention allows for theeconomical mass production and commercialization of a high performancebowel cleansing composition.

As the bowel cleansing composition of the present invention hasexcellent cleansing efficacy, ease of administration and safety, it canbe utilized for bowel preparation prior to colonoscopy or the like, forpreparation prior to colonic surgery and anal surgery for hemorrhoid orthe like as well as for the treatment and alleviation of diseases suchas chronic and acute constipation.

The present invention will now be described in more detail withreference to examples. It is to be understood, however, that theexamples are provided to illustrate embodiments of the present inventionand not intended to limit the scope of the invention.

Example 1

In 100 mL of distilled water as solvent, 45 g of xylitol, 25 g ofascorbic acid, 20 mg of picosulfate, 200 mg of simethicone, 1.4 g ofsodium bicarbonate, 3.4 g of potassium bicarbonate, and 20 mg ofsucralose were mixed to form 150 mg of a highly concentrated solution,and 350 ml of carbonated water was used as a separate vehicle to preparea two-part bowel cleansing composition.

Mixing was conducted by mixing all the ingredients in powder form at thesame time and then pouring solvent to dissolve them. Caution is neededbecause a large amount of carbon dioxide (CO₂) gas generated by theneutralization reaction between the acidic ascorbic acid and basicbicarbonate salt causes extensive foaming. Preparing a 1:10 dilutedsolution of Gasocol® containing the anti-foaming agent simethiconebeforehand and adding it suitably while mixing can successfully preventfoaming, thereby facilitating the mixing process. Since a pharmaceuticalsimethicone product containing about 30% of silicon is insoluble inwater, Gasocol®, which is a liquid formulation comprising simethicone asthe main component, was used instead in this example.

<Comparative Reference Example 1>

For in vitro tests to assess the safety of sugar alcohols used as afirst cleansing ingredient in the present invention, ComparativeReference Example 1 was prepared for comparison with the solution ofExample 1.

Comparative Reference Example 1 refers to a 10 mL PICOLYTE solutionwhich is prepared by diluting the active ingredient in bottled wateraccording to the recommended regimen. The concentration of the activeingredient is the same as its concentration used in bowel cleansing.

<Experimental Example 1: Safety tests concerning the production ofcombustible gases (in vitro)>

Measurement of concentrations of hydrogen and methane gases

With regard to safety tests regarding the production of intestinalcombustible gases, it is not easy to obtain suitable specimens from thesubject or assess colonic gas during colonoscopy and it is notreasonable to conclude that the observed differences are attributable tothe difference in the bowel cleansing solution based only on resultsobtained from a limited number of cases while the conditions ofindividual subjects after bowel preparation are widely different. Thus,the potential risk of the composition prepared in the Example wasindirectly investigated by in vitro tests which can be conducted underidentical conditions.

For this purpose, aliquots of the solutions from Example 1, ComparativeReference Example 1, and Control (bottled water) were mixed with adiluted solution of stool collected from 5 people, and 20 mL of thediluted solution each was stored in 500 mL containers for 18 hours atroom temperature. Then, gas concentrations in each container weremeasured using a gas detector. The diluted solutions of stool wereprepared by sampling stools from fiver different subjects and diluting 3g of the stool from each subject in 100 mL of bottled water, giving atotal of 5 different diluted solutions of stool.

Detailed test protocols are described below.

For each of the five subjects whose stool samples were taken, a 10 mLaliquot of the diluted solution of stool was placed in three containers,providing three containers holding the same diluted solution of stool.As a result, a total of 15 containers holding the diluted solutions ofstool from the five subjects were prepared.

For each subject, 10 ml each of the test solutions from Example 1,Comparative Reference Example 1 (PICOLYTE), and Control (bottled water)were added to the three containers holding the same diluted solution ofstool, respectively.

After mixing the diluted solutions of stool with the respective testsolutions, the containers were sealed by tight capping and stored for 18hours at room temperature.

Then, the concentrations of hydrogen and methane in each container weremeasured using the Geotech GA5000 gas analyzer (Landtech, UK). GeotechGA5000 gas analyzer can measure methane in vol % unit and hydrogen inthe range of 0-1000 ppm.

Measurement of the gas concentrations in the 15 containers in total gaveaverage measurements for the concentrations of the combustible gases,hydrogen and methane, as shown in Table 1.

TABLE 1 Comparative Reference Control Example 1 (Bottled Example 1(PICOLYTE) water) Hydrogen (ppm) 0 451.3 173.6 Methane (Vol %) 0.13 0.160.14

As can be seen from Table 1, the bowel cleansing composition of Example1 gave no detectable hydrogen, as well as a methane concentration of0.13%, which is lower than that of the control and that of thepicosulfate bowel cleansing solution of Comparative Reference Example 1.That is, these results show that the bowel cleansing composition of thepresent invention is the safest with respect to the generation ofcolonic combustible gases.

Bacterial Culture Test

Following the measurement of gas concentration as described above, themixed solutions in the containers were submitted to two testinginstitutions, i.e., a laboratory at the Seoul Medical Science Institute(SCL), a CAP accredited and Korean Society for Laboratory Medicine(KSLM)/Laboratory Medicine Foundation accredited institution, and theKSLM accredited Green Cross Laboratories, where they were cultured for48 hours and measured for the resulting colony counts.

Averages of the colony counts for the respective test solutions arelisted in Table 2. In addition, FIG. 1 and FIG. 2 show the results fromthe culture of intestinal bacterial for Example 1, Comparative ReferenceExample 1, and Control, in accordance with the respective laboratories.

TABLE 2 Comparative Reference Control Example 1 (bottled Example 1(PICOLYTE) water) Colony SCL 2.2 3.1 2.8 counts Green Cross 14.5 302.233.1 (CFU/mL) Laboratories (Unit: 10⁵ CFU/ml)

The above colony count results clearly demonstrate the antibacterialeffect of the bowel cleansing composition according to the presentinvention. Specifically, in case of Example 1, the colony counts of thecultures of the diluted solutions of stool in the five subjects were alllower than those of Comparative Reference Example 1 using PICOLYTE andeven those of the Control group. That is, it can be seen from Example 1that bacteria capable of producing combustible gases such as hydrogen ormethane were significantly suppressed. Although obtained from in vitrotests, these results demonstrate that with respect to the production ofcombustible gases in the colon, the bowel cleansing composition of thepresent invention is safer than any of the existing bowel cleansingagents.

With respect to Comparative Reference Example 1 in which PICOLYTE wasused, it was found that the counts of the cultured colonies were higherthan those of the Control group in natural state. This has not yetbecome an issue but suggests the potential risk of this type of bowelcleansing agent to promote the generation of combustible gas. Theseresults show that the bowel cleansing agent of the present invention isvery safe with respect to the generation of combustible gas although itcontains a sugar alcohol.

The above results demonstrate that the composition of Example 1comprising xylitol, ascorbic acid, and picosulfate as main ingredientsis very safe with regard to intestinal bacterial growth and theresulting production of combustible gases in the colon.

Such excellent antibacterial effect suggest that the bowel cleansingcomposition of the present invention may greatly contribute to reducingthe incidence of postoperative infections when it is used as a laxativefor bowel preparation before colonic surgery. Because contamination fromthe bowel contents may occur during colonic surgery, the preoperativeadministration of antibiotics to prevent surgical site infection due tosuch contamination is established as the standard. However, if the bowelcleansing composition of the present invention is used for preoperativebowel preparation, it inhibits bacteria in the bowel contents, reducingthe possibility of infection even when contamination from the bowelcontents occurs.

Considering the fact that the existing bowel cleansing liquids are usednot only for bowel cleansing prior to colonoscopy but also as the mainlaxative for preoperative bowel preparation before colonic surgery, theabove-described effect may enhance the significance of the bowelcleansing composition of the present invention.

From the two in vitro safety tests described above, it can be seen thatthe novel bowel cleansing composition according to the present inventionhas the lowest risk as it minimizes the production of combustiblehydrogen and methane gases compared to conventional colon cleansingpreparations and inhibits bacterial growth.

Comparative Examples 1 and 2

Comparative Examples 1 and 2 were prepared for comparative experimentsconcerning the ease of administration, bowel cleansing efficacy andsafety of the bowel cleansing composition of the present invention.

Specifically, for in vivo experiments, commercially available bowelcleansing products PICOLYTE and CoolPrep were respectively mixed withwater in their recommended mixing amounts to prepare the bowel cleansingcompositions for Comparative Examples 1 and 2. The identities of thebowel cleansing agents and the volume of water used in ComparativeExamples 1 and 2 are listed in Table 3.

TABLE 3 Bowel cleansing agent Volume of water Comparative PICOLYTE 2pouches 2.3 L Example 1 Comparative CoolPrep 4 pouches 3 L (includingExample 2 1 L water for additional ingestion) PICOLYTE: Pharmbio KoreaCo., Ltd., 16.37 g per pouch CoolPrep: Taejoon Pharm Co., Ltd., 56.402 gper pouch

The bowel cleansing compositions prepared in Example 1 and ComparativeExamples 1 and 2 were evaluated for their cleansing performance andcompliance.

Specifically, the bowel cleansing efficacy, ease of administration, andsafety of Comparative Example 1 (n=63), Comparative Example 2 (n=49),and Example 1 (n=161) were evaluated in patients undergoing colonoscopy.Detailed dosing regimens for Example 1 and Comparative Examples 1 and 2are described below.

In the dosing regimen of Example 1, starting from 5 hours before thescheduled examination, a total of 500 ml of the bowel cleansing solutionwas ingested at a rate of 100 ml (5 mouthfuls, one half of a paper cup)every 30 minutes for a total of 5 times as a general rule. Afteringestion of 100 ml of the bowel cleansing solution, 200 ml of bottledwater was additionally ingested every 15 minutes. According to thisregimen, ingestion of the bowel cleansing agent took 120 minutes intotal.

With respect to Comparative Example 1, i.e., PICOLYTE 2.3 L, one pouchprovided in the product was ingested after dilution in 150 ml of waterat 7 PM the day before the examination followed by additional 1 L ofwater over one hour, and the process was repeated once on the day ofexamination at 5 hours before starting the examination.

With respect to Comparative Example 2, i.e., CoolPrep 3 L, 1 L of theprepared solution was ingested over 1 hour (250 ml of solution every 15minutes) at 7 PM the day before the examination, and another 1 L of theprepared solution was ingested over 1 hour on the day of examination at5 hours before starting the examination. The patients were instructed todrink 500 ml of water in the evening and morning of the day ofexamination after completing the ingestion of the diluted solution.

<Experimental Example 2: Bowel Cleansing Efficacy>

Bowel cleansing efficacy was assessed in two aspects: {circle around(1)} colon cleanliness and {circle around (2)} the amount of bubbles.

Colon Cleanliness

For the assessment of colon cleanliness, a surgeon evaluated the levelof colon cleanliness of a patient using a five-point scale (Excellent,Good, Fair, Poor, Fail) according to the criteria shown in Table 4 andFIG. 3. For a fair evaluation, the evaluation was carried out in a blindtest in which the surgeon performing the colonoscopy was not informed ofthe identity of the bowel cleansing composition consumed by theindividual patients.

TABLE 4 Excellent Very thorough cleansing allowing the detection of evensmall lesions Good Slightly less clean than “Excellent” whilesufficiently clean to allow the detection of even small lesions FairPossible to miss one or two lesions ≤5 mm Poor Possible to miss lesions≥5 mm due to poor cleanliness but no possibility of missing malignantlesions, i.e., colon cancer Fail Requiring repeat preparation because ofthe possibility of missing malignant lesions, i.e., colon cancer

The results of the colon cleanliness assessment according to thecriteria show in Table 4 and FIG. 3 are provided in Table 5.

TABLE 5 Colon cleanliness (%) Sample Excellent Good Fair Poor FailExample 1 36.7 55.7 5.7 1.9 0 Comparative 15.9 41.3 22.1 15.9 4.8Example 1 (PICOLYTE) Comparative 16.3 51 22.5 10.2 0 Example 2(CoolPrep)

FIG. 4A and FIG. 4B present the above results classified as “effectivebowel cleansing” referring to conditions adequate for colonoscopy and“insufficient bowel preparation” referring to conditions unsatisfactoryor impossible for accurate colonoscopy. “Effective bowel preparation”includes conditions rated as Excellent or Good, and “insufficient bowelpreparation” includes conditions rated as Fair, Poor, or Fail.

As can be seen from Table 5, FIG. 4A and FIG. 4B, the rate of effectivebowel preparation was the highest in Example 1 as 92.4%, whileComparative Example 2 was found to be the worst in cleanliness with arate of effective bowel cleansing of 57.2%. Comparative Example 2 showeda rate of effective bowel cleansing of 67.3%. These results fairlycorrespond with reports in some foreign research articles indicatingthat the PEG preparations and phosphate preparations show rates ofadequate bowel cleansing of about 70˜75% <“Colonoscopy preparation”,ASGE technology committee, GASTROINTESTINAL ENDOSCOPY,69(No.7):1201-1209, 2009>.

However, insufficient bowel preparation as is seen with ComparativeExamples 1 and 2 actually causes serious problems because it does notallow for accurate colonoscopy. Normally, colonoscopy is repeated every4-5 years. If the results of colonoscopy performed after a painful bowelpreparation are inaccurate such that polyps or early colon cancer arenot detected, the diseases are usually neglected for 4-5 years until thenext screening examination, potentially allowing for polyps to advanceto cancer or for the early colon cancer to advanced colon cancer.

Amount of Bubbles

In addition to colon cleanliness, another major factor for accuratecolonoscopy is the presence of bubbles in the colon. Almost all bowelcleansing agents tend to generate bubbles in the colon following bowelpreparation. Accordingly, the prevention or removal of such bubbles isrequired in order to thoroughly inspect the colonic lumen to detect evensmall lesions. The presence or absence as well as the extent of bubbleswere observed after ingestion of the bowel cleansing composition ofExample 1 and Comparative Examples 1 and 2, and the results are shown inTable 6. The extent of bubbles were rated on a three-point scale of“None,” “Some,” and “Substantial.” FIG. 5 is a photograph showing asubstantial amount of intracolonic bubbles generated after theconsumption of the bowel cleansing composition of Comparative Example 1.

TABLE 6 Amount of bubbles (%) Sample None Some Substantial Example 192.8 7.2 0 Comparative 35.7 33.9 30.4 Example 1 (PICOLYTE) Comparative32.5 27.5 40 Example 2 (CoolPrep)

As shown in the above results, in case of Example 1, bubbles were notgenerated in 92.8% of the subjects, but in case of Comparative Examples1 and 2, the percentage of subjects developing no bubbles was as low asabout ⅓. In particular, substantial amounts of bubbles were formed tothe extent that examination was greatly interfered in more than one inthree subjects. When bubbles form, they can be washed away usingpharmaceutical agents during colonoscopy. However, it takes asubstantial amount of effort and time as the area that can be washed atone time is limited. Thus, excessive bubble formation interferes withthe smooth progress of colonoscopy and also becomes the reason formissing small lesions. As for the bowel cleansing composition of Example1, the almost complete prevention of bubble formation allows for moretime to be allotted to the observation of lesions while at the same timereducing procedure time, and also enhances the disease detection ratebecause the clear vision facilitates the detection of small lesions.

<Experimental Example 3: Ease of Administration>

Ease of administration was assessed in four aspects: {circle around (1)}taste of the cleansing agent, {circle around (2)} discomfort afteradministration, {circle around (3)} willingness to recommend to family,and {circle around (4)} need for improvement.

Taste of Cleansing Agents

In a questionnaire, the subjects were asked to subjectively rate thetaste of the bowel cleansing agents on a three-point scale of “Veryunpleasant,” “slightly unpleasant,” and “Fair.: The percentages of eachresponse category are shown in Table 7.

TABLE 7 Taste of bowel cleansing compositions (%) Sample Very unpleasantSlightly unpleasant Fair Example 1 0 4.9 95.1 Comparative 0 6.1 93.9Example 1 (PICOLYTE) Comparative 14.3 53.1 32.6 Example 2 (CoolPrep)

As shown in the above results, 95.1% of the subjects rated the taste ofthe bowel cleansing agent as “Fair” for Example 1, while 93.9% of thesubjects rated the taste of the bowel cleansing agent as “Fair” forComparative Example 1. For Comparative Example 2, however, only 32.6% ofthe subjects rated the taste of the bowel cleansing agent as “Fair”.

Discomfort after Administration

Discomforts after administration were classified into 4 groups ofabdominal pain, bloating, vomiting, and thirst. In a questionnaire, thesubjects were asked to indicate self-perceived discomforts, and thepercentages of each response category are shown in Table 8.

TABLE 8 Discomfort after administration (%) Sample Abdominal painBloating Vomiting Thirst Example 1 8 28 2 25 Comparative 17 38 2 27Example 1 (PICOLYTE) Comparative 10.4 10.4 37.5 18.8 Example 2(CoolPrep)

As can be seen from Table 8, Example 1 caused a level of discomfort thatis lower than or similar to existing bowel cleansing agents with regardto all categories such as abdominal pain, bloating, vomiting, andthirst. Vomiting was quite frequent in Comparative Example 2, whichappears to be associated with the unpleasant taste of PEG preparations.

Willingness to Recommend

In a questionnaire, subjects were asked if they are willing to recommendthe bowel cleansing composition they used to their family, and thepercentages of subjects who answered negatively are shown in Table 9.

TABLE 9 Sample Non-recommendation (%) Example 1 2 Comparative 7 Example1 (PICOLYTE) Comparative 53 Example 2 (CoolPrep)

As shown in the above results, the percentage of non-recommendation wasquite high (53%) in case of Comparative Example 2.

Meanwhile, Comparative Example 1 showed a relatively lower percentage ofnon-recommendation with a rate of 7%, which is slightly higher than thatof Example 1. This may be viewed as being associated with its largevolume of ingestion amounting to 2.3 L.

Need for Improvement

In a questionnaire, the subjects were asked if the bowel cleansing agentthey used needs improvement, and the percentages of subjects whoanswered affirmatively are shown in Table 10.

TABLE 10 Need for Sample improvement (%) Example 1 5 Comparative 7Example 1 (PICOLYTE) Comparative 58 Example 2 (CoolPrep)

From the above results, it can be seen that Example 1 shows the highestsatisfaction as the percentage of subjects who saw the need forimprovement is the lowest. In comparison, 7% of the subjects saw theneed for improvement in Comparative Example 1 and 58% of the subjectssaw the need for improvement in Comparative Example 2.

Patient Preferences for Example 1 and Other Bowel Cleansing Agents

Among the subjects who were given the bowel cleansing composition ofExample 1, 89 subjects who had previously experienced colon preparationwere asked if the ease of administration was enhanced compared to theirprevious colon preparation experiences. The results are shown in Table11.

TABLE 11 Percentage of subjects having experience with other RelativeEase of Use bowel cleansing agents (%) Easier Much easier 57.4 Slightlyeasier 21.3 Comparable 21.3 More difficult 0

As can be seen from the above results, 78.7% of the subjects who hadexperienced other bowel cleansing agents replied that consumption of thebowel cleansing composition of Example 1 was easier, while none of thesubjects found it more difficult. These results allows for an indirectcomparison between the existing bowel cleansing agents in ComparativeExamples 1 and 2 and the preparation of Example 1, which shows asignificantly favorable preference for the preparation of Example 1.

<Experimental Example 4: Safety (In Vivo Test)>

The safety of each bowel cleansing agent was assessed by conductingblood tests for the blood ascorbic acid concentration, and bloodchemistry.

Colonic Gas Measurement

With respect to the production of combustible gases, further to theabove in vitro test showing the safety of the bowel cleansingcomposition of the present invention, for each of the 10 subjects whoused the bowel cleansing composition of Example 1, actual colonic gascollected during their colonoscopy was analyzed. The results showed thatthe methane concentration was 0.10.3 vol % and the hydrogenconcentration was 1-7 ppm, directly demonstrating that theconcentrations of these gases are in no way close to their minimumexplosive concentrations, i.e., 5% and 4,000 ppm, respectively.

Blood Ascorbic Acid Concentration

Following the consumption of the bowel cleansing compositions, bloodsamples were taken from subjects just before their colonoscopy, and theblood ascorbic acid concentrations were measured at the SCL (SeoulMedical Science Institute), a testing institution equipped withapparatus for measuring ascorbic acid blood levels. The resultingaverage values are listed in Table 12.

TABLE 12 Average blood ascorbic acid concentration Sample (referencerange: 2-20 μg /mL) Example 1 32.4 Comparative 6.9 Example 1 (PICOLYTE)Comparative 30.4 Example 2 (CoolPrep)

The reference range for blood ascorbic acid concentration is 2-20 μg/mL.It can be expected that the blood ascorbic acid concentration istransiently elevated above the reference range with Comparative Example3 where 21.2 g of ascorbic acid is mixed in the ingested liquid as wellas with Example 1 containing 25 g of ascorbic acid compounds. However,since ascorbic acid is water soluble, blood ascorbic acid exceeding thereference value is directly excreted via the kidney to reduce the bloodconcentration to normal.

In addition, the U.S. National Cancer Institute has officially confirmedthat high dose ascorbic acid is not harmful to the human body(http://www.cancer.gov/cancertopics/pdq/cam/highdosevitaminc/healthprofessional/pagel/AllPages).

Since the 1970s, many studies have been conducted to determine if anintravenous injection of high dose ascorbic acid has therapeutic effectson various cancers. While there is no consensus on its therapeuticeffect, it was confirmed along the way that except for people with G6PDdeficiency, renal disorders or urolithiasis, up to 1.5 g/kg of ascorbicacid can be safely administered intravenously to a healthy person“Vitamin C pharmacokinetics: implications for oral and intravenous use”,Padayatty S J, Sun H, Wang Y, et al., Ann Intern Med 140 (7), 533-7,2004; “Phase I clinical trial of i.v. ascorbic acid in advancedmalignancy”, Hoffer L J, Levine M, Assouline S, et al., Ann Oncol 19(11), 1969-74, 2008>.

It was also reported in a phase I clinical study conducted in 2013 thatascorbic acid 15 g given intravenously over 30 minutes twice weekly forfour weeks elevated the blood ascorbic acid level to at least 350 mg/dL(3,500 μg/mL), yet was very well tolerated and caused no severe adverseeffects <“Pharmacological ascorbate with gemcitabine for the control ofmetastatic and node-positive pancreatic cancer (PACMAN): results from aphase I clinical trial”, Welsh J L, Wagner B A, van't Erve T J, et al.,Cancer Chemother Pharmacol 71 (3), 765-75, 2013>

The above information is found in official resources published on thewebsite of the U.S. National Cancer Institute, confirming that highblood ascorbic acid concentration causes no harm to human health. Inaddition, the above-referenced ascorbic acid blood concentration of3,500 μg/mL is almost 175 times the upper limit of its reference rangeand 108 times as high as 32.4 μg/mL, the average blood ascorbic acidconcentration observed after using the bowel cleansing composition ofExample 1. That is, it can be seen that the elevation of ascorbic acidconcentration after consuming the bowel cleansing composition of Example1 does no harm to human health.

It is believed that for these reasons, MoviPrep® was able to be approvedby the U.S. FDA as a bowel cleansing agent without difficulty despitehaving the same composition as CoolPrep (used in Comparative Example 2),which has been shown to cause transient elevation of the blood ascorbicacid level.

Other Blood Chemistry Test

As other blood chemistry tests, magnesium concentrations, electrolyteconcentrations, concentrations of blood urea nitrogen (BUN) andcreatinine, which are indicators of kidney functions, as well as liverenzymes AST (GPT) and ALT (GPT) reflecting liver damage were measuredand the results are shown in Tables 13-16. Blood was collected rightbefore the colonoscopy and measurements were taken at the Department ofLaboratory Medicine at Joyful Hospital following the usual protocol.

TABLE 13 Mg (reference range: Samples 1.58-2.55 mg/dL) Example 1 2.1Comparative 2.5 Example 1 (PICOLYTE) Comparative 2.2 Example 2(CoolPrep)

TABLE 14 Na K Cl (reference range: (reference range: (reference range:Samples 135-145 mmol/L) 3.5-5.5 mmol/L) 98-110 mmol/L) Example 1 140.74.5 104.5 Comparative 140.3 4.0 102.2 Example 1 (PICOLYTE) Comparative144.9 4.6 108.2 Example 2 (CoolPrep)

TABLE 15 BUN Creatinine (reference range: (reference range: Samples 5-23mg/dL) 0.5-1.2 mg/dL) Example 1 10.8 0.7 Comparative 11.8 0.8 Example 1(PICOLYTE) Comparative 12.4 0.8 Example 2 (CoolPrep)

TABLE 16 AST(GOT) ALT(GPT) (reference range: (reference range: Samples0-32 IU/L) 0-31 IU/L) Example 1 24.4 24.5 Comparative 24.6 25.7 Example1 (PICOLYTE) Comparative 28 24.3 Example 2 (CoolPrep)

As can be seen from the above results, except for the fact thatmagnesium concentration was 2.5 mg/dL which is close to its upper limit(reference range 1.58˜2.55 mg/dL) in subjects receiving the bowelcleansing composition of Comparative Example 1, no abnormalities wereobserved in the results for the concentrations of electrolytes, kidneyfunction indicators BUN and creatinine, and liver enzymes AST and ALT,for all of the bowel cleansing agents.

The reason the magnesium blood concentration was elevated close to itsupper limit in patients receiving the bowel cleansing composition ofComparative Example 1 is because a large amount of magnesium oxide (10.5g) is included in PICOLYTE.

To sum up, it has been shown that like other bowel cleansing agents, thebowel cleansing composition of Example 1 is a safe pharmaceuticalpreparation which does not cause hematochemical abnormalities.

INDUSTRIAL APPLICABILITY

By combining specific concentrations of a sugar alcohol, ascorbic acid,and picosulfate, the bowel cleansing composition according to thepresent invention displays superior cleansing efficacy as well asimproved taste compared to existing bowel cleansing agents. The bowelcleansing composition according to the present invention also greatlyenhances the ease of administration and compliance by significantlyreducing the volume of ingestion. In addition, the bowel cleansingcomposition according to the present invention improves patientdiscomfort by minimizing discomforts during its consumption such asnausea, abdominal pain and vomiting. By incorporating bicarbonates suchas sodium bicarbonate, potassium bicarbonate, etc., it can preventelectrolyte abnormalities such as hyponatremia, hypopotassemia, etc.,which can occur with the existing picosulfate-containing bowel cleansingagents. Since the bowel cleansing composition of the present inventiondoes not contain any magnesium, it can be safely used in patients withrenal disorders with no severe side effects.

1.-19. (canceled)
 20. A bowel cleansing composition, comprising: (i) a first cleansing component comprising at least one type of sugar alcohol selected from xylitol, sorbitol, glycerol, erythritol, thrithol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, maltotaglytol, and polyglycitol; (ii) a second cleansing component comprising ascorbic acid or a mixture of ascorbic acid and ascorbic acid salt; and (iii) a water-soluble solvent, wherein the concentration of said first cleansing component is 10 g/L to 500 g/L, wherein the concentration of said second cleansing component is 15 g/L to 500 g/L, and wherein the volume of said water-soluble solvent is 0.1L-1.0L.
 21. The bowel cleansing composition of claim 20, wherein said composition further comprises a third cleansing component comprising bisacodyl at a concentration of 5 mg/L to 50 mg/L.
 22. The bowel cleansing composition of claim 21, wherein said third cleansing component is included in the form of a suspension.
 23. The bowel cleansing composition of claim 20, wherein said composition further comprises an anti-foaming agent at a concentration of 100 mg/L to 2 g/L, wherein said anti-foaming agent is simethicone.
 24. The bowel cleansing composition of claim 20, wherein said composition further comprises bicarbonate selected from sodium bicarbonate and potassium bicarbonate, wherein said sodium bicarbonate concentration is 0.1 g/L to 10 g/L, and wherein said potassium bicarbonate concentration is 0.1 g/L to 20 g/L.
 25. The bowel cleansing composition of claim 20, wherein said composition further comprises a gastrointestinal tract stabilizer selected from ginger, mint, and chamomile, wherein said gastrointestinal tract stabilizer concentration is 5 g/L to 50 g/L.
 26. The bowel cleansing composition of claim 20, wherein said first cleansing component is xylitol.
 27. The bowel cleansing composition of claim 20, wherein said first cleansing component is sorbitol.
 28. The bowel cleansing composition of claim 20, wherein said first cleansing component is a mixture of xylitol and sorbitol.
 29. The bowel cleansing composition of claim 20, wherein when said second cleansing ingredient is a mixture of ascorbic acid and ascorbic acid salt, the mass ratio of ascorbic acid to ascorbic salt ranges from 99:1 to 60:40.
 30. The bowel cleansing composition of claim 20, wherein said water-soluble solvent is water, carbonated water, alkaline ionic water, or a beverage.
 31. The bowel cleansing composition of claim 20, wherein said water-soluble solvent is carbonated water.
 32. The bowel cleansing composition of claim 20, wherein the concentration of said first cleansing component is 50 g/L to 150 g/L.
 33. The bowel cleansing composition of claim 20, wherein the concentration of said second cleansing component is 30 g/L to 200 g/L.
 34. The bowel cleansing composition of claim 20, wherein the volume of said water-soluble solvent is 0.3L to 0.7L.
 35. The bowel cleansing composition of claim 20, wherein said composition is a one-part product.
 36. The bowel cleansing composition of claim 20, wherein said composition is two-part product.
 37. The bowel cleansing composition of claim 36, wherein (i) the first part of said two-part product is a package containing a highly concentrated solution formulated by mixing the bowel cleansing components of claim 20 in 0.05L to 0.2L of said water-soluble solvent; and (ii) the second part of said two-part product is a separate package containing the remaining amount of said water-soluble solvent that is its total volume minus the volume used in formulating the highly concentrated solution. 